Clotrimazole Enemas for Pouchitis in Children and Adults

Colectomy with creation of an ileal pouch (IPAA) is now the treatment of choice for patients
with ulcerative colitis that is resistant to existing medical therapies. The development of
inflammation in these ileal reservoirs, a clinical entity referred to as pouchitis, is the
most common long-term complication of this procedure and can affect 50-60% of adults and
children. We have previously demonstrated that clotrimazole (delivered as a rectal
suppository) is generally safe, effective, and displays poor systemic absorption when used in
pediatric and adults with active pouchitis. We saw clinical benefit in patients with pouch
disease that had previously failed to respond to standard antibiotic, steroid, or
immunosuppressive therapies. The clinical trial outlined here will define the effectiveness
and safety of topical clotrimazole therapy (delivered as a rectal enema) in pediatric (aged
greater than two years) and adult patients with pouchitis.

Subjects in this study will be randomly assigned to receive either placebo (no active drug, 4
subjects) or one of two clotrimazole therapy groups: 2500 mg/day (8 subjects) or 4000mg/day
(8 subjects). No washout period is required, and subjects will be allowed to continue their
existing anti-inflammatory medications during their participation in the study. Clotrimazole
will be delivered nightly in the form of an enema. Subjects will undergo flexible
sigmoidoscopy (pouchoscopy) prior to and again after completing one month of study therapy,
and pouch disease activity will be graded at after each procedure using the Pouchitis Disease
Activity Index (PDAI). Clinical improvement will be defined as a drop in PDAI score. If the
drop in PDAI scores between placebo and either active clotrimazole treatment group is not
significant, and no subject experiences what are determined to be study-related adverse
effects, a second cohort of subjects will be recruited and studied after receiving one month
of either placebo (4 subjects), 6000 mg/day clotrimazole (8 subjects), or 7500mg/day
clotrimazole (8 subjects).

Subjects will be assessed for adverse effects at the midpoint of the study. Clotrimazole
blood levels will be measured during the first and last day of study participation. In
addition, adults will complete a health related quality of life assessment at baseline and
after completing study drug therapy.

All subjects will be eligible for one month of open-label study drug therapy after completing
one month of study drug therapy.